Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00017 (IFN-gamma)
 28,919 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To characterize the requirements for the induction of an anergic state in immunocompetent cells we examined the effect of an increase in intracellular calcium concentration on the subsequent responsiveness of cytolytic T cells to antigenic stimulation in vitro. Pretreatment of a murine cytolytic T cell clone with the calcium-ionophore A23187 resulted in the induction of an anergic state characterized by a decrease in cytolytic activity and granule exocytosis upon Ag-specific stimulation. Furthermore, IFN-gamma synthesis declined whereas de novo synthesis of a yet unidentified protein with a molecular mass of 33 kDa as well as proliferative response of cells in response to exogenous IL-2 were unaffected. This state of partial unresponsiveness 1) could be prevented by concomitant pretreatment of cells with cyclosporin A or protein synthesis inhibitors and 2) was reversible within 48 h. Biochemical analysis of TCR-induced intracellular activation revealed a block in signal transduction before the activation of protein kinase C because cellular unresponsiveness could be bypassed by the phorbol ester PMA plus the calcium-ionophore A23187. However, phosphatidylinositol turnover was markedly inhibited in unresponsive cells that also did not show a calcium influx on stimulation with concanavalin A. We conclude that a rise in intracellular calcium in cytolytic T cells might not only be necessary for cellular activation but may also trigger the induction of a partial unresponsiveness to antigenic stimulation due to an inhibition in the early phase of signal transduction.
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PMID:Functional and biochemical characterization of a calcium-ionophore-induced state of unresponsiveness in a cytolytic T cell clone. 131 47

The effects of different recombinant human cytokines and cytokine inhibitors were compared in a culture system in which cell contact with mutant EL-4 thymoma cells of murine origin efficiently stimulates human B cell proliferation and Ig secretion in conjunction with human T cell supernatant. IL-1 alpha, IL-1 beta, TNF-alpha, and IL-2 co-stimulated B cell proliferation and IgM, IgG, and IgA secretion, whereas IL-3, IL-4, IL-5, IL-6, IFN-gamma, or GM-CSF had weak or no activity in this regard. In contrast, TGF-beta 1 was strongly inhibitory. A very strict hierarchy of cytokine interactions was found in that IL-1 was necessary to induce TNF-alpha responsiveness, and TNF-alpha the IL-2 responsiveness, of the B cells. Most likely the small number of starting B cells in the present assay (300 FACS-separated B cells/200 microliters) minimized the effects of autocrine B cell factors. IL-4 together with IL-1 induced IgE secretion, and the IgE secretion was further increased by TNF-alpha. IFN-gamma had no modulatory effect on the IL-4 dependent IgE response in this system. Pretreatment of B cells with IL-1R antagonist (IL-1ra, which binds to IL-1R) or addition of soluble TNF receptor type 1 (sTNF-R55, which binds to TNF) completely inhibited the IL-1 or TNF-alpha effects, respectively. This occurred in a specific manner; the inhibition was reversed by a large excess of cytokine. IL-1ra also inhibited a B cell response induced by PMA-preactivated EL-4 cells alone. Because B cells responding to such preactivated EL-4 cells did not acquire TNF-alpha responsiveness, no IL-1 was apparently involved under this assay condition. It appears, therefore, 1) that IL-1ra can act on B cells and 2) that this antagonist may not only block IL-1R, but may provide a direct or indirect inhibitory signal interfering even with IL-1-independent B cell activation.
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PMID:Effects of eleven cytokines and of IL-1 and tumor necrosis factor inhibitors in a human B cell assay. 131 59

To investigate the relationship between cytokine production and the increased levels of serum IgE and peripheral eosinophilia commonly accompanying human helminth infections, we studied the ability of PBMC of normal (N1) (n = 18) and eosinophilic individuals with helminth infections (H1) (n = 9) to produce IL-3, IL-4, IL-5, granulocyte-macrophage-CSF, and IFN-gamma in vitro after stimulation with PMA (50 ng/ml) and ionomycin (1 microgram/ml). The two groups differed in both the levels of serum IgE and eosinophilia. For mitogen-induced production of granulocyte-macrophage-CSF and IFN-gamma, there was no difference in cytokine production between the two groups. In marked contrast, supernatants from PBMC of infected individuals had significantly higher levels of IL-4 (mean = 213 pg/ml for N1 and 944 pg/ml for H1, p less than 0.02), IL-5 (mean = 180 pg/ml for N1 and 1118 pg/ml for HL, p less than 0.001), and IL-3 (mean = 13900 pg/ml for N1, 28029 pg/ml for H1, p less than 0.05). In addition, helminth-infected patients had approximately 5-fold greater numbers of T cells capable of producing IL-5 and 2.5-fold greater frequency of IL-4-secreting cells than did normal individuals; GM-CSF- and IFN-gamma-producing T cell numbers were not significantly different in the two groups. IL-3-producing cell frequencies could not be evaluated by this method. There was a direct correlation between IL-4 production and IL-5 production at the level of both protein production and frequency of T cells capable of producing these cytokines. These data indicate that individuals with reactive eosinophilia and elevated serum IgE have an expanded population of lymphocytes producing IL-4 and IL-5 and the association of the two suggests that the regulation of IL-4 and IL-5 may be linked.
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PMID:Parallel regulation of IL-4 and IL-5 in human helminth infections. 135 Feb 92

Herpetic stromal keratitis (HSK) appears to represent an immunopathologic response in the cornea of the eye to HSV-1. T cells of the CD4+ subset were shown to be involved in the mediation of HSK, but how they subserve an immunopathologic role is uncertain. In the present report, we have isolated cells from eyes in the active phase of HSK and studied their cytokine profile after culture in vitro or stimulation with Ag or nonspecific mitogens. Inflammatory cells recovered from eyes consist of polymorphonuclear leukocytes, macrophages, and lymphocytes. As reported before, all the lymphocyte recovered were of the CD4+ phenotype. After stimulation in vitro with Ag or mitogen the cytokines IL-2, IFN-gamma, and TNF-alpha/beta were produced, but not the cytokines IL-4 and IL-10. Thus, on the basis of cytokine profile, ocular lymphocytes were identified as Th1 cells. Ocular cells were also stimulated with PMA and shown to produce IL-1. The results were discussed in terms of the possible means by which the Th1 cells induce tissue damage in HSK as well as in terms of the possible means by which a preferential accumulation of Th1 cell occurs in the eye.
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PMID:Predominance of Th1 cells in ocular tissues during herpetic stromal keratitis. 135 34

Recent studies have suggested that certain oncogenes, in particular members of the myc family, may be involved in the down-regulation of HLA class-I antigen expression observed in many types of tumor. We report that constitutive expression of an OK10 v-myc gene in human monoblastic U-937 cells results in a reduced expression of HLA class-I cell-surface expression and decreased levels of HLA class-I protein and mRNA. All class-I alleles, with the possible exception of HLA A3, were affected, as shown by one-dimensional isoelectric focusing (ID-IEF). Basal expression of the beta 2m chain was also reduced, although to a lesser extent. In addition, we show that the PMA-, and at least partially the IFN-alpha-induced increase in HLA class-I antigen expression, was inhibited in U-937-myc cells both at the protein and the mRNA level. In contrast, the response to IFN-gamma was normal. Another important difference in the response to IFN-gamma and alpha was that, while IFN-gamma abrogated the v-myc block of PMA-induced differentiation of U-937 cells, as previously reported, IFN-alpha did not. Our data show that v-myc negatively affects the regulation of both basal and inducible HLA class-I antigen expression.
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PMID:Suppression of basal, PMA- and IFN-alpha-, but not IFN-gamma-induced expression of HLA class I in v-myc-transformed U-937 monoblasts. 135 27

The preferential growth of CD3-CD2-CD11a/CD18- thymocytes was obtained by stimulation of CD2-CD3- thymic cells with low doses of PMA (0.5 ng/ml) and subsequent culture in the presence of recombinant interleukin-2 (100 U/ml). After 2-3 weeks, CD3-CD2-CD11a/CD18- thymocytes represented 40-60% of the total proliferating cells. Highly purified CD3-CD2-CD11a/CD18- cell populations were obtained by depletion of the CD11a/CD18+ thymocytes by immunomagnetic beads. Moreover, these populations proliferated for 2-5 weeks and did not change their surface phenotype. It is of note that these cells, despite the lack of CD2 and CD11a/CD18 adhesion molecules, could bind to umbilical vein endothelial cells as efficiently as did CD3+CD2+CD11a/CD18+ thymocytes. Furthermore we demonstrate that (a) CD56 molecule is involved in the adhesion of CD3-CD2-CD11a/CD18- thymic cells, but not of peripheral CD3-CD56+ lymphocytes, to untreated or IFN-gamma- and/or TNF-alpha-treated endothelium, (b) anti-CDw49d mAb could inhibit the adhesion of this thymus-derived population to either IFN-gamma- or TNF-alpha-treated endothelial cells but not to untreated endothelium, and (c) CD56 antigen expressed by these cultured thymocytes has a sialic acid content different from that of peripheral lymphocytes. Indeed, isoelectrofocusing analysis showed that CD56 molecule expressed on CD3-CD2-CD11a/CD18- thymocytes displayed an isoelectric point (pI 5.0) different from that of CD56 antigen expressed by peripheral NK cells (pI 4.7 and 5.4). Further, we noted that CD56 antigen showed the same pI 5.8 after desialylation obtained using neuraminidase treatment. Finally, CD3-CD2-CD11a/CD18- thymocytes mobilized Ca2+ and released TNF-alpha and IFN-gamma after treatment with lectins.
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PMID:Cultured human thymocytes lacking CD2 and CD11a/CD18 antigens are functional and adhere to endothelial cells via CD56 or CDw49d molecules. 137 47

The CD20 molecule is a unique phosphoprotein exclusively expressed on B cells during most stages of B cell ontogeny. We here report that rIL-4 down-regulates the expression of CD20 with anti-Leu-16 mAb (clone L27) on both unstimulated and anti-mu preactivated normal and leukemic B cells. None of the other recombinant lymphokines tested (IL-1, IL-2, IL-3, IL-6, IFN-alpha, and IFN-gamma, granulocyte/macrophage-CSF, transforming growth factor-beta, TNF-alpha, and lymphotoxin) decreased CD20 expression. Incubation of unstimulated or anti-mu preactivated B cells with IL-4 did not affect the steady state CD20 mRNA, suggesting that IL-4 exerted its effect mainly at a nontranscriptional level. Hence, IL-4 selectively down-regulates the CD20 epitope recognized by clone L27 without affecting seven other different epitopes, indicating that IL-4 acts by modifying the conformation of the CD20 molecule rather than by inhibiting its production or inducing its internalization. IL-4 most likely utilizes a protein kinase C-independent signal transduction pathway to modify CD20 molecule inasmuch as staurosporine, an inhibitor of protein kinase C, antagonizes phorbol esters (PMA) but not IL-4-induced CD20 down-regulation. In contrast, anti-CD40 mAb reverses the IL-4 but not the PMA inhibitory effect on CD20 expression. Given that CD20 may be part of a Ca2+ ion channel and plays a role in B cell activation and proliferation, it is proposed that the ability of anti-CD40 mAb to maintain the CD20 molecule in a given epitopic configuration on IL-4-stimulated B cells may be related to the long term proliferation of normal B cells that are strictly dependent on the presence of IL-4 and cross-linked anti-CD40 mAb for their continuous growth.
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PMID:IL-4 induces conformational change of CD20 antigen via a protein kinase C-independent pathway. Antagonistic effect of anti-CD40 monoclonal antibody. 137 68

The interferon (IFN)-gamma-induced indoleamine 2,3-dioxygenase (IDO) is implicated in the inhibition of intracellular pathogens, e.g. Chlamydia psittaci and Toxoplasma gondii. The intracellular signaling molecules responsible for the induction of IDO gene expression were investigated by the quantitative polymerase chain reaction. The gene expression was inhibited by a tyrosine kinase inhibitor, genistein. Being consistent with this, IFN-gamma induced increased tyrosine phosphorylation and this was inhibited by genistein. The transcription of IDO gene was not inhibited by protein kinase C (PKC) inhibitors, H-7 and staurosporine, or a calmodulin inhibitor, W-7. Irrelevance of PKC in IDO gene expression was supported by the failure of PMA or PMA + A23187 to induce IDO gene expression. These results all suggest that the tyrosine phosphorylation is a critical event in IFN-gamma-inducible IDO gene expression and PKC is not involved in the gene expression.
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PMID:[The signal transduction mechanism responsible for interferon-gamma-inducible indoleamine 2,3-dioxygenase (IDO) gene expression in T98G cells]. 146 78

We have advanced the hypothesis that the primary autolymphoproliferative response of dog T cells in mixed lymphocyte kidney cultures (MLKC) results from their recognition of tissue-specific (kidney-associated) antigen(s) presented in conjunction with class II MHC antigens. Lymphocyte culture-derived supernatants had been found previously to upregulate class II antigen expression on kidney cells and enhance T cell activation. In the present study we have isolated and characterized dog IFN-gamma, a class II-inducing substance that is secreted in the culture supernatant of activated T lymphocytes. Dog IFN-gamma was induced with A-23187 and PMA and purified stepwise using controlled-pore glass, Mono Q anion exchange chromatography, and Superose 6-gel filtration on FPLC. The purification resulted in two molecules of 42 Kd and 31 Kd molecular weights. An IgG1 monoclonal antibody was engendered to these molecules. With this mAb reagent, in immunochemical experiments, we have developed a sensitive ELISA and a method for purifying dog IFN-gamma by affinity chromatography. Species specificity studies indicated that purified dog IFN-gamma reacted with a polyclonal rabbit antihuman IFN-gamma, but not with a mAb to human IFN-gamma. However, the antidog IFN-gamma mAb that was generated also reacted with recombinant human IFN-gamma. In in vitro biological studies, the purified IFN-gamma (two mol. wt. species) upregulated the expression of canine class II MHC molecules on dog tubular epithelial cells and the dog kidney epithelial cell line (MDCK). The antidog IFN-gamma mAb blocked T cell proliferative response to kidney cell and, by inference, the interaction between endogenously released IFN-gamma in vitro with its cell surface receptor, thus inhibiting the induced upregulation of class II. Interestingly, although antidog IFN-gamma markedly blocked the MLKC (10 micrograms mAb/well), there was no effect on the allogeneic MLC. This observation indicates that the cytokine IFN-gamma may be a uniquely key substance amplifying the immune response of T cells to tissue-associated antigens on surrogate antigen-presenting cells that require induced upregulation of class II MHC antigen expression (MLKC), in contrast to reactions in which these antigens are already constitutively expressed on the antigen-presenting cells (mixed lymphocyte culture).
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PMID:Immunochemical and biochemical characterization of purified canine interferon-gamma. Production of a monoclonal antibody, affinity purification, and its effect on mixed lymphocyte culture and mixed lymphocyte kidney culture reactions. 153 Oct 93

The regulation of extracellular matrix (ECM) protein receptor expression was followed in the human promonocytic cell line U937 before and after stimulation either with PMA or various cytokines implicated in monocytopoiesis. On undifferentiated U937 cells, alpha-chains of very late Ag (VLA)-4, VLA-5, and VLA-6 were constitutively expressed whereas alpha-chains of VLA-2 (alpha 2) and vitronectin receptor (alpha V) were not. Maturation of U937 cells with PMA resulted in a marked decrease in alpha 4 expression (25% of control by day 5), and a small but significant increase in the expression of alpha 2 and alpha v over 4 days of stimulation. Unstimulated U937 cells attached to fibronectin (FN) but not to laminin (LM), collagens I/IV-coated surfaces. After PMA stimulation, U937 cells exhibited enhanced adherence on FN and expressed the ability to adhere to LM. PMA stimulation also promoted U937 spreading both on FN and LM. Adhesion on FN all along the maturation pathway was specifically and totally inhibited by anti-alpha 5 mAb but not by anti-alpha 4 mAb. Anti-beta 1, anti-alpha 6, anti-alpha 2, and anti-alpha v mAb, as well as Tyr-Ile-Gly-Ser-Arg and Arg-Gly-Asp synthetic peptides from LM, had no effect on adhesion of PMA-stimulated cells on LM, implying that U937 cell adherence to LM is mediated through hitherto distinct receptors. In the presence of rIFN-gamma, differentiating U937 cells did not adhere to LM and lost the capacity to bind to FN. Loss of adhesion to FN was correlated with the concomitant decrease in the expression of alpha 4 and alpha 5 integrin subunits. In contrast, TGF-beta 1 mimicked most of the effects of PMA by enhancing the attachment of maturating U937 cells on FN through alpha 5 receptors and by promoting adherence to LM. TGF-beta 1 stimulation also promoted U937 cell spreading on both FN- and LM-coated surfaces. The data suggest that inflammatory cytokines such as IFN-gamma and TGF-beta 1 may be critically important in the homing of monocytic cells at sites of inflammation by modulating cell-surface expression of ECM receptors.
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PMID:IFN-gamma and transforming growth factor-beta 1 differently regulate fibronectin and laminin receptors of human differentiating monocytic cells. 153 26


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